The observation that approximately 35% of breast cancers are estrogen dependent has stimulated research into methods of limiting estrogen production. Initial efforts were to surgically remove the primary source of estrogen (ovaries) or the primary sources of their biosynthetic steroid precursors, the androgens (adrenal glands). While these methods are often successful, work has been directed in recent years towards a more effective inhibition of estrogen production in a nonintrusive, less traumatic way. (Abul-Hajj, Y. J., J. Steroid Biochem., 13 1395 (1980); Brodie, A. M. H., Cancer Res., 42, 3312s (1982); Brodie, A. M. H.; Brodie, H. J.; Garrett, W. H.; Hendrickson, J. R.; Marsh, D. A.; and Tsai-Morris, Chon-Hwa, Biochem. Pharm., 31, 2017 (1982); and Powles, T. J., Seminars in Oncology, 10, suppl. 4, 20 (1983).) Inhibition of the last enzymatic step, the aromatization of the A.sup.4,3-keto androgens to the phenolic estrogens, would seem the most effective and least disruptive based upon knowledge of the enzymes involved in the biosynthesis of estrogens from cholesterol. The enzyme responsible for this conversion is a unique cytochrome P-450 monooxygenase complex known as "aromatase" (Brodie, A. M. H., J. Endocrinol. Invest., 2, 445 (1979)) that requires O.sub.2 and NADPH to catalyze three sequential hydroxylations of the androgen precursor followed by a spontaneous chemical aromatization of the A ring to yield the phenolic estrogens. A proposed mechanism for aromatase activity is shown in FIG. 1.
Based upon this mechanism, others (Marcotte, P. A., and Robinson, C. H., Biochemistry, 21, 2773 (1982); Flynn, G. A.; Johnston, J. O.; Wright, C. L.; and Metcalf, B. W., Biochem. Biophys. Res. Comm., 103, 913 (1981); and Metcalf, B. W.; Wright, C. L.; Burhart, J. P.; and Johnston, J. O., J. Am. Chem. Soc., 103, 3221 (1981)) have proposed suicide inhibitors for aromatase. Troner (Cancer Res., 42, 3402s-3404s (1982)) and Powles et al. (The Lancet, June 23, 1984, 1369-1372) suggest aminoglutethimide (AG), a competitive inhibitor, with other compounds to treat metastatic breast cancers. AG, however, is a sedative which has the side effect of lethargy. Also, AG is not specific to aromatase, so it disrupts enzymatic pathways other than the androgen-estrogen pathway.
Menard et al. (Mol. Pharm., 16, 997 (1979)) discloses thiol steroids as suicide inhibitors of P-450 steroid hydroxylase activity.
Hormonal treatment of tumors and steroid research are active fields with great promise. The appropriate inhibitors should be specific to the enzyme pathway where inhibition is sought. Thus, the synthetic hormones of the present invention offer promise, as will be explained.